This application is a 371 of PCT/SE00/01251 filed Jun. 15, 2000.
This invention relates to novel pharmaceutically useful compounds, in particular compounds which are useful in the treatment of cardiac arrhythmias.
Cardiac arrhythmias may be defined as abnormalities in the rate, regularity, or site of origin of the cardiac impulse or as disturbances in conduction which causes an abnormal sequence of activation. Arrhythmias may be classified clinically by means of the presumed site of origin (i.e. as supraventricular, including atrial and atrioventricular, arrhythmias and ventricular arrhythmias) and/or by means of rate (i.e. bradyarrhythmias (slow) and tachyarrhythmias (fast)).
In the treatment of cardiac arrhythmias, the negative outcome in clinical trials (see, for example, the outcome of the Cardiac Arrhythmia Suppression Trial (CAST) reported in New England Journal of Medicine, 321, 406 (1989)) with xe2x80x9ctraditionalxe2x80x9d antiarrhythmic drugs, which act primarily by slowing the conduction velocity (class I antiarrhythmic drugs), has prompted drug development towards compounds which selectively delay cardiac repolarization, thus prolonging the QT interval. Class III antiarrhythmic drugs may be defined as drugs which prolong the trans-membrane action potential duration (which can be caused by a block of outward K+ currents or from an increase of inward ion currents) and refractoriness, without affecting cardiac conduction.
One of the key disadvantages of hitherto known drugs which act by delaying repolarization (class III or otherwise) is that they all are known to exhibit a unique form of proarrhythmia known as torsades de pointes (turning of points), which may, on occasion be fatal. From the point of view of safety, the minimisation of this phenomenon (which has also been shown to be exhibited as a result of administration of non-cardiac drugs such as phenothiazines, tricyclic antidepressants, antihistamines and antibiotics) is a key problem to be solved in the provision of effective antiarrhythmic drugs.
Antiarrhythmic drugs based on bispidines (3,7-diazabicyclo[3.3.1]nonanes), are known from inter alia international patent application WO 91/07405, ye European patent applications 306 871, 308 843 and 655 228 and US Pat. Nos. 3,962,449, 4,556,662, 4,550,112, 4,459,301 and 5,468,858, as well as journal articles including inter alia J. Med. Chem. 39, 2559, (1996), Pharmacol. Res., 24, 149 (1991), Circulation, 90, 2032 (1994) and Anal. Sci. 9, 429, (1993). Known bispidine-based antiarrhythmic compounds include bisaramil (3-methyl-7-ethyl-9xcex1, 4xe2x80x2-(Cl-benzoyloxy)-3,7-diazabicyclo[3.3.1]nonane), tedisamil (3xe2x80x2, 7xe2x80x2-bis(cyclopropylmethyl)spiro-(cyclopentane-1,9xe2x80x2)-3,7-diazabicyclo[3.3.1]nonane), SAZ-VII-22 (3-(4-chlorobenzoyl)-7-isopropyl-3,7-diazabicyclo[3.3.1]nonane), SAZ-VII-23 (3-benzoyl-7-isopropyl-3,7-diazabicyclo[3.3.1]nonane), GLG-V-13 (3-[4-(1H-imidazol-1-yl)benzoyl]-7-isopropyl-3,7-diazabicyclo[3.3.1]nonane), KMC-IV-84 (7-[4xe2x80x2-(1H-imidazol-1-yl)benzenesulfonyl]-3-isopropyl-3,7-diaza-bicyclo[3.3.1]nonane dihydroperchlorate and ambasilide (3-(4-aminobenzoyl)-7-benzyl-3,7-diazabicyclo[3.3.1]nonane).
We have surprisingly found that a novel group of bispidine-based compounds exhibit electrophysiological activity, preferably class III electrophysiological activity, and are therefore expected to be useful in the treatment of cardiac arrhythmias.
According to the invention there is provided compounds of formula I, 
wherein
R1 represents C1-12 alkyl, xe2x80x94(CH2)a-aryl, or xe2x80x94(CH2)a-Het1 (all of which are optionally substituted and/or terminated (as appropriate) by one or more substituents selected from xe2x80x94OH, halo, cyano, nitro, C1-4 alkyl and/or C1-4 alkoxy);
a represents 0, 1, 2, 3, or 4;
Het1 represents a five to ten-membered heterocyclic ring containing one or more heteroatoms selected from oxygen, nitrogen and/or sulfur, and which also optionally includes one or more xe2x95x90O sub stituents;
X represents O or S;
R5a and R5b independently represent H or C1-3 alkyl;
R2 and R3 independently represent H, C1-4 alkyl (optionally substituted and/or terminated with one or more nitro or cyano groups), OR7, N(R7a)R7b, OC(O)RS or together form xe2x80x94Oxe2x80x94(CH2)2xe2x80x94Oxe2x80x94, xe2x80x94(CH2)3xe2x80x94, xe2x80x94(CH2)4xe2x80x94 or xe2x80x94(CH2)5xe2x80x94;
R7 and R8 independently represent H, C1-6 alkyl or xe2x80x94(CH2)b-aryl (which latter two groups are optionally substituted and/or terminated by one or more substituents selected from xe2x80x94OH, halo, cyano, nitro, C1-4 alkyl and/or C1-4 alkoxy);
R7a and R7b independently represent H or C1-6 alkyl;
b represents 0, 1, 2, 3 or 4;
R4 represents H or C1-6 alkyl;
R9 represents xe2x80x94C(O)R10, C1-6 alkyl, xe2x80x94(CH2)d-aryl or xe2x80x94(CH2)d-Het2 (which latter three groups are optionally substituted by one or more substituents selected from xe2x80x94OH, halo, cyano, nitro, C1-4 alkyl, C1-4 alkoxy, C(O)R11, C(O)OR12 and/or xe2x80x94N(H)S(O)eR13);
R10, R11 and R12 independently represent H, C1-6, alkyl, Het3 or xe2x80x94(CH2)f-aryl (which latter three groups are optionally substituted and/or terminated (as appropriate) by one or more substituents selected from xe2x80x94OH, cyano, halo, amino, nitro, C1-6, alkyl, C1-6 alkoxy, C(O)R14, C(O)OR15 and/or N(H)S(O)2R16);
R13 represents C1-6 alkyl or xe2x80x94(CH2)g-aryl (both of which are optionally substituted and/or terminated (as appropriate) by one or more substituents selected from halo, nitro, C1-6 alkyl and/or C1-6 alkoxy);
R14 and R15 independently represent H, C1-6 alkyl or aryl;
R16 represents C1-6 alkyl or aryl;
e represents 0, 1 or 2;
d, f and g independently represent 0, 1, 2, 3 or 4;
Het2 and Het3 independently represent five to ten-membered heterocyclic rings containing one or more heteroatoms selected from oxygen, nitrogen and/or sulfur, and which also optionally includes one or more xe2x95x90O substituents;
R6 represents one or more optional substituents selected from xe2x80x94OH, cyano, halo, amino, nitro, C1-6 alkyl (optionally terminated by N(H)C(O)OR18a), C1-6 alkoxy, xe2x80x94C(O)N(H)R19, xe2x80x94NHC(O)N(H)R20, xe2x80x94N(H)S(O)2R21 and/or xe2x80x94OS(O)2R22;
R19 and R20 independently represent H or C1-6 alkyl;
R18a, R21 and R22 independently represent C1-6 alkyl;
A represents a single bond, C1-6 alkylene or xe2x80x94(CH2)jC(H)(OR23)(CH2)kxe2x80x94 (in which latter group, the xe2x80x94(CH2)jxe2x80x94 group is attached to the bispidine nitrogen atom and which latter two groups are optionally substituted by one or more xe2x80x94OH groups);
B represents a single bond, C1-4 alkylene, xe2x80x94(CH2)mN(R24)xe2x80x94, xe2x80x94(CH2)mS(O)nxe2x80x94, xe2x80x94(CH2)mOxe2x80x94 (in which three latter groups, the xe2x80x94(CH2)mxe2x80x94 group is attached to the carbon atom bearing OR9 and R4), xe2x80x94C(O)N(R24)xe2x80x94 (in which latter group, the xe2x80x94C(O)xe2x80x94 group is attached to the carbon atom bearing OR9 and R4), xe2x80x94N(R24)C(O)O(CH2)mxe2x80x94 or xe2x80x94N(R24)(CH2)mxe2x80x94 (in which latter two groups, the N(R24) group is attached to the carbon atom bearing OR9 and R4);
j represents 1, 2, 3 or 4;
k and m independently represent 0, 1, 2, 3 or 4;
n represents 0, 1 or 2;
R23 represents H, C1-6 alkyl or C(O)R25; 
R24 represents H or C1-6 alkyl;
R25 represents H, C1-6 alkyl, Het4 or xe2x80x94(CH2)p-aryl (which latter two groups are optionally substituted and/or terminated (as appropriate) by one or more substituents selected from xe2x80x94OH, cyano, halo, amino, nitro, C1-6 alkyl and/or C1-6 alkoxy);
Het4 represents a five to ten-membered heterocyclic ring containing one or more heteroatoms selected from oxygen, nitrogen and/or sulfur, and which also optionally includes one or more xe2x95x90O substituents;
p represents 0, 1, 2, 3 or 4;
or a pharmaceutically acceptable derivative thereof;
provided that m does not represent 0 when B represents xe2x80x94(CH2)mN(R24), xe2x80x94(CH2)mS(O)nxe2x80x94 or xe2x80x94(CH2)mOxe2x80x94,
which compounds are referred to hereinafter as xe2x80x9cthe compounds of the inventionxe2x80x9d.
Aryl groups that may be mentioned include C6-10 aryl groups, such as phenyl, naphthyl and the like. Oxyaryl groups that may be mentioned include C6-10 oxyaryl groups, such as oxyphenyl (phenoxy), oxynaphthyl (naphthoxy) and the like. When substituted, aryl and aryloxy groups are preferably substituted by between one and three substituents.
Het1, Het2, Het3 and Het4 groups that may be mentioned include those containing 1 to 4 heteroatoms (selected from the group oxygen, nitrogen and/or sulfur) and in which the total number of atoms in the ring system is between five and ten. Het (Het1, Het2, Het3 and Het4) groups may be wholly/partly aromatic in character and may be bicyclic and/or include one or more xe2x95x90O substituents. Heterocyclic groups that may be mentioned include morpholinyl, thiazolyl, oxazolyl, isoxazolyl, cinnolinyl, quinazolinyl, phthalazinyl, purinyl, benzimidazolyl, pyrimindinyl, piperazinyl, pyrazinyl, piperidinyl, pyridinyl, pyrrolinyl, pyrrolidinyl, pyrollidinonyl, triazolyl, imidazolyl, quinolinyl, isoquinolinyl, dioxanyl, benzodioxanyl, benzodioxolyl, benzodioxepanyl, benzomorpholinyl, indolyl, pyrazolyl, pyrrolyl, benzothiophenyl, thiophenyl, chromanyl, thiochromanyl, benzofuranyl, pyranyl, tetrahydropyranyl, tetrahydrofuranyl, furanyl and the like. Values of Het2 that may be mentioned include pyridinyl. Values of Het3 that may be mentioned include piperazinyl (which latter group is optionally substituted by one or more C(O)R14 and/or C(O)OR15 group). Substituents on Het (Het1, Het2, Het3 and Het4) groups may, where appropriate, be located on any atom in the ring system including a heteroatom. The point of attachment of Het (Het1, Het2, Het3 and Het4) groups may be via any atom in the ring system including (where appropriate) a heteroatom. Het may optionally be in the N- or S-oxidised form.
Pharmaceutically acceptable derivatives include salts and solvates. Salts which may be mentioned include acid addition salts. Pharmaceutically acceptable derivatives also include C1-4 alkyl quaternary ammonium salts and N-oxides, provided that, when a N-oxide is present:
(a) no Het (Het1, Het2, Het3, Het4) groups contain an unoxidised S-atom;
(b) X does not represent S; (c) n does not represent 0, when B represents xe2x80x94(CH2)mS(O)nxe2x80x94; and/or (d) e does not represent 0, when R9 is substituted by xe2x80x94N(H)S(O)eR13.
The compounds of the invention may exhibit tautomerism. All tautomeric forms and mixtures thereof are included within the scope of the invention.
The compounds of the invention may also contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism. Diastereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation. The various stereoisomers may be isolated by separation of a racemic or other mixture of the compounds using conventional, e.g. fractional crystallisation or HPLC, techniques. Alternatively the desired optical isomers may be made by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation or epimerisation, or by derivatisation, for example with a homochiral acid followed by separation of the diastereomeric esters by conventional means (e.g. HPLC, chromatography over silica). All stereoisomers are included within the scope of the invention. Alkyl groups that R1, R2, R3, R4, R5a, R5b, R6, R7, R7a, R7b, R8, R9, R10, R11, R12, R13, R14, R15, R16, R18a, R19, R20, R21, R22, R23, R24 and R25 may represent, and with which R1, R7, R8, R9, R10, R11, R12, R13 and R25 may be substituted; and alkoxy groups that R6 may represent, and with which R1, R7, R8, R9, R10, R11, R12, R13 and R25 may be substituted, may be linear or, when there is a sufficient number (i.e. three) of carbon atoms, be branched and/or cyclic. Further, when there is a sufficient number (i.e. four) of carbon atoms, such alkyl and alkoxy groups may also be part cyclic/acyclic. Such alkyl and alkoxy groups may also be saturated or, when there is a sufficient number (i.e. two) of carbon atoms, be unsaturated and/or interrupted by oxygen and/or substituted by one or more fluoro groups.
Alkylene groups that A and B may represent, and xe2x80x94(CH2)xe2x80x94 containing groups that R1, R2 and R3 (together), R7, R8, R9, R10, R11, R12, R13, R25, A and B may include, may be linear or, when there is a sufficient number (i.e. two) of carbon atoms, be branched. Such alkylene groups and xe2x80x94(CH2)xe2x80x94 containing chains may also be saturated or, when there is a sufficient number (i.e. two) of carbon atoms, be unsaturated and/or interrupted by oxygen.
As used herein, the term xe2x80x9chaloxe2x80x9d includes fluoro, chloro, bromo or iodo.
Abbreviations are listed at the end of this specification.
According to a further aspect of the invention there is provided compounds of formula I as hereinbefore defined, except that B does not represent xe2x80x94N(R24)C(O)O(CH2)mxe2x80x94 or xe2x80x94N(R24)(CH2)mxe2x80x94.
Preferred compounds of the invention include those in which:
R1 represents optionally substituted xe2x80x94(CH2)a-phenyl, in which a is 0, 1, 2 or 3, or, preferably, optionally substituted, optionally unsaturated, linear, branched or cyclic, C1-8 alkyl (which latter group may also be interrupted by an oxygen atom);
R2 represents H;
R3 represents H;
R4 represents H or C1-2 alkyl; R5a and R5b either both represent H or both represent methyl;
R6 represents one or more substituents selected from C1-6alkyl, cyano, nitro, amino, C(O)N(H)R19 and/or xe2x80x94N(H)S(O)2R21;
X represents O;
A represents a single bond or linear, or branched, C1-6 alkylene (which group is also optionally interrupted by O);
B represents a single bond, C1-4 alkylene, xe2x80x94(CH2)mOxe2x80x94 or xe2x80x94(CH2)mN(R24)xe2x80x94 (in which latter two cases m is 1, 2 or 3);
R9 represents C(O)R10 (in which R10 represents C1-3 alkyl or optionally substituted Het3); C13 alkyl; optionally substituted phenyl; or optionally substituted xe2x80x94(CH2)d-Het2 (in which d is 0, 1 or 2);
when the bispidine nitrogen bearing A optionally bears a C1-4 alkyl group, thus forming a quaternary ammonium salt, the alkyl group is a methyl group.
More preferred compounds of the invention include those in which:
R1 represents linear or branched C2alkyl;
R4 represents H;
R5a and R5b both represent H;
R6 represents cyano, preferably in the para position relative to B;
A represents Cl4 alkylene;
B represents a single bond;
R9 represents C(O)R10 (in which R10 represents C1-2 alkyl or 1,4-piperazinyl (optionally substituted in the 4-position by a C(O)R14 or a C(O)OR15 group)); C1-2 alkyl; phenyl (optionally substituted by one or more groups selected from C1-2 alkoxy, OH, halo and/or N(H)S(O)2R13 (in which R13 is C1-2 alkyl); or xe2x80x94(CH2)d-Het2 (in which d represent 0 or 1 and Het2 represents pyridinyl, optionally in the form of an N-oxide).
Preferred compounds of the invention include the compounds of Examples described hereinafter.
According to the in vention there is also provided a process for the preparation of compounds of formula I which comprises:
(a) reaction of a compound of formula II, 
wherein R2, R3, R4, R5a, R5b, R6, R9, A and B are as hereinbefore defined with a compound of formula III,
R1XC(O)L1xe2x80x83xe2x80x83III
wherein L1 represents a leaving group, such as Hal, imidazolyl or xe2x80x94OC(O)XR1, Hal represents Cl, Br or I, and R1 and X are as hereinbefore defined, for example at or above room temperature in the presence of a suitable base (e.g. aqueous. NaOH, K2CO3 or triethylamine) and an appropriate organic solvent (e.g. CH2Cl2, THF, acetonitrile, toluene, or mixtures of such solvents);
(b) reaction of a compound of formula IV 
wherein R1, R2, R3, R5a, R5b and X are as hereinbefore defined, with a compound of formula V, 
wherein L2 represents a leaving group (e.g. mesylate, tosylate or Hal, where Hal is as hereinbefore defined) and R4, R6, R9, A and B are as hereinbefore defined, for example at elevated temperature (e.g. between 35xc2x0 C. and reflux temperature) in the presence of a suitable base (e.g. triethylamine or K2CO3) and an appropriate organic solvent (e.g. acetonitrile or dimethylsulfoxide);
(c) for compounds of formula I in which R2 and R3 both represent H, reduction of a corresponding compound of formula VI, 
wherein R1, R4, R5a, R5b, R6, R9, A, B and X are as hereinbefore defined, and in which the bridgehead Cxe2x95x90O group may be activated using an appropriate agent, such as tosylhydrazine, in the presence of a suitable reducing agent (e.g. sodium borohydride or sodium cyanoborohydride) and an appropriate organic solvent (e.g. a lower alkyl alcohol); when the Cxe2x95x90O group is activated, the activation step may be carried out at between room and reflux temperature in the presence of an appropriate organic solvent (e.g. a lower alkyl alcohol such as methanol, ethanol or IPA), whereafter the reducing agent may be added to the reaction mixture and the reduction carried out at between 60xc2x0 C. and reflux, advantageously in the presence of a suitable organic acid (e.g. acetic acid);
(d) for compounds of formula I in which one or R2 and R3 represents H and the other represents xe2x80x94OH, reduction of a corresponding compound of formula VI, as hereinbefore defined, in the presence of a mild reducing agent, e.g. sodium borohydride, and an appropriate organic solvent (e.g. a lower alcohol such as methanol or ethanol);
(d) for compounds of formula I in which one or R2 and R3 represents H and the other represents xe2x80x94OH, reduction of a corresponding compound of formula VI, as hereinbefore defined, in the presence of a mild reducing agent, e.g. sodium borohydride, and an appropriate organic solvent (e.g. a lower alcohol such as methanol or ethanol);
(e) for compounds of formula I in which R9 represents optionally substituted C1-6 alkyl, optionally substituted xe2x80x94(CH2)d-aryl or optionally substituted xe2x80x94(CH2)d-Het2, reaction of a compound of formula VII, 
wherein R1, R2, R3, R4, R5a, R5b, R6, A, B and X are as hereinbefore defined with a compound of formula VIII,
R9aOH xe2x80x83xe2x80x83VIII
wherein R9a represents optionally substituted C1-6alkyl, optionally substituted xe2x80x94(CH2)d-aryl or optionally substituted xe2x80x94(CH2)d-HeO, wherein d and Het2 are as hereinbefore defined, for example at between ambient (e.g. 25xc2x0 C.) and reflux temperature, under Mitsunobu-type conditions (i.e. in the presence of e.g. triphenylphosphine, an azodicarboxylate derivative (e.g. 1,1xe2x80x2-(azodicarbonyl)dipiperidine) and a suitable organic solvent (e.g. dichloromethane));
(f) for compounds of formula I in which R9 represents optionally substituted C1-6 alkyl, optionally substituted xe2x80x94(CH2)d-aryl or optionally substituted xe2x80x94(CH2)d-Het2, reaction of a compound of formula IX, 
wherein L2, R1, R2, R3, R4, R5a, R5b, R6, A, B and X are as hereinbefore defined with a compound of formula VIII as hereinbefore defined, for example at between ambient (e.g. 25xc2x0 C.) and reflux temperature, under Williamson-type conditions (i.e. in the presence of an appropriate base (e.g. KOH or NaH) and a suitable organic solvent (e.g. dimethylsulfoxide or DMF));
(g) for compounds of formula I in which R9 represents C(O)R10 and R10 is as hereinbefore defined, reaction of a corresponding compound of formula VII as hereinbefore defined and a compound of formula X,
R10CO2Hxe2x80x83xe2x80x83X
wherein R10 is as hereinbefore defined, for example at ambient temperature i (e.g. 25xc2x0 C.) in the presence of a suitable coupling agent (e.g. 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide), an appropriate catalyst (e.g. 4-dimethylaminopyridine) and a reaction-inert organic solvent (e.g. THF);
(h) for compounds of formula I in which R2 and/or R3 represent OC(O)R8 and R8 is as hereinbefore defined, coupling of a corresponding compound of formula I in which R2 and/or R3 (as appropriate) represents OH and a compound of formula XI,
R8CO2Hxe2x80x83xe2x80x83XI
wherein R8 is as hereinbefore defined, for example at ambient temperature (e.g. 25xc2x0 C.) in the presence of a suitable coupling agent (e.g. 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide), an appropriate catalyst (e.g. 4-dimethylaminopyridine) and a reaction-inert organic solvent (e.g. THF);
(i) for compounds of formula I which are bispidine-nitrogen N-oxide derivatives, oxidation of the corresponding bispidine nitrogen of a corresponding compound of formula I, in the presence of a suitable oxidising agent (e.g. m-chloroperbenzoic acid), for example at 0xc2x0 C. in the presence of a suitable organic solvent (e.g. DCM);
(j) for compounds of formula I which are C1-4 alkyl quaternary ammonium salt derivatives, in which the alkyl group is attached to a bispidine nitrogen, reaction, at the bispidine nitrogen, of a corresponding compound of formula I with a compound of formula XII,
RxHalxe2x80x83xe2x80x83XII
wherein Rx represents C1-4 alkyl and Hal is as hereinbefore defined, for example at room temperature in the presence of an appropriate organic solvent (e.g. DMF), followed by purification (using e.g. HPLC) in the presence of a suitable counter-ion provider (e.g. NH4OAc);
(k) reaction of a compound of formula II, as hereinbefore defined, with a compound of formula XIII,
R1XHxe2x80x83xe2x80x83XIII
wherein R1 and X are as hereinbefore defined, in the presence of 1,1xe2x80x2-carbonyldiimidazole, for example by refluxing in the presence of a suitable organic solvent (e.g. THF); or
(1) for compounds of formula I in which one or both of R2 and R3 represent xe2x80x94N(R7a)R7b in which one or both or R7a and R7b represents C1-6 alkyl, alkylation of a corresponding compound of formula I in which R2 and/or R3 represent xe2x80x94N(R7a)R7b (as appropriate) in which R7a and/or R7b (as appropriate) represent H, using a compound of formula XIIIA,
R7cL1xe2x80x83xe2x80x83XIIIA
wherein R7c represents C1-6 alkyl and L1 is as hereinbefore defined, for example under conditions that are well known to those skilled in the art; or
(m) conversion of one R6 substituent to another using techniques well known to those skilled in the art.
Compounds of formula II may be prepared by reaction of a compound of formula XIV, 
wherein R2, R3, R5a and R5b are as hereinbefore defined, with a compound of formula V as hereinbefore defined, for example as described hereinbefore for synthesis of compounds of formula I (process step (b)).
Compounds of formula II in which R2 and R3 both represent H may be prepared by reduction of a compound of formula XV, 
wherein R4, R5a, R5b, R6, R9, A and B are as hereinbefore defined, and in which the Cxe2x95x90O group may be activated using an appropriate agent, such as tosylhydrazine, for example as described hereinbefore for synthesis of compounds of formula I (process step (c)).
Compounds of formula II in which R2 represents OH and R3 represents optionally substituted C1-4 alkyl, may be prepared by reaction of a compound of formula XV, or a protected derivative thereof, with a compound of formula XVI,
R3aMgHalxe2x80x83xe2x80x83XVI
wherein R31represents C1-4 alkyl (optionally substituted and/or terminated with one or more cyano groups) and Hal is as hereinbefore defined, for example at between xe2x88x9225xc2x0 C. and ambient temperature in the presence of a suitable solvent (e.g. diethyl ether).
Compounds of formula IV may be prepared by reaction of a compound of formula XIV, as hereinbefore defined, with a compound of formula III as hereinbefore defined, for example as described hereinbefore for synthesis of compounds of formula I (process step (a)).
Compounds of formula IV may alternatively be prepared by reaction of a compound of formula XIV, as hereinbefore defined, with a compound of formula XIII, as hereinbefore defined, in the presence of 1,1xe2x80x2-carbonyldiimidazole, for example as described hereinbefore for synthesis of compounds of formula I (process step (k)).
Compounds of formula IV in which R2 and R3 represent H may alternatively be prepared by reduction of a corresponding compound of formula XVII, 
wherein R1, R5a, R5b and X are as hereinbefore defined, and in which the bridgehead Cxe2x95x90O group may be activated using an appropriate agent, such as tosylhydrazine, for example as described hereinbefore for compounds of formula I (process step (c)).
Compounds of formula V may be prepared by standard techniques. For example compounds of formula V in which:
(1) B represents xe2x80x94(CH2)mOxe2x80x94 may be prepared by coupling a compound of formula XVIII, 
wherein R6 is as hereinbefore defined, to a compound of formula XIX,
L4xe2x80x94(CH2)mxe2x80x94C(OR9)(R4)xe2x80x94Axe2x80x94L2xe2x80x83xe2x80x83XIX
wherein L4 represents a suitable leaving group (e.g. Hal) and Hal, m, R4, R9, A and L2 are as hereinbefore defined;
(2) B represents xe2x80x94C(O)N(R24)xe2x80x94 may be prepared by coupling a compound of formula XX, 
wherein R6 and R24 are as hereinbefore defined, to a compound of formula XXI,
L4xe2x80x94C(O)xe2x80x94C(OR9)(R4)xe2x80x94Axe2x80x94L2xe2x80x83xe2x80x83XXI
wherein L4, R4, R9, A and L2 are as hereinbefore defined;
in both cases, under conditions which are well known to those skilled in the art.
Compounds of formula V in which A represents C2-alkylene and R9 represents optionally substituted C1-6 alkyl, optionally substituted xe2x80x94(CH2)dxe2x80x94 aryl or optionally substituted xe2x80x94(CH2)d-Het2 may alternatively be prepared by reaction of a compound of formula VIII as hereinbefore defined with a compound of formula XXII, 
wherein Ry represents C1-4 alkyl or aryl (which two groups are optionally substituted with one or more substituents selected from C1-4 alkyl or halo) and R4, R6 and B are as hereinbefore defined, for example at between ambient temperature (e.g. 25xc2x0 C.) and reflux temperature in the presence of a suitable base (e.g. K2CO3) and an appropriate organic solvent (e.g. acetonitrile), followed by conversion of the ester functionality to an L2 group (in which L2 is as hereinbefore defined), under conditions that are well known to those skilled in the art.
Compounds of formula V in which B represents xe2x80x94(CH2)mS(O)xe2x80x94 or xe2x80x94(CH2)mS(O)2xe2x80x94 may be prepared by oxidation of a corresponding compound of formula V wherein B represents xe2x80x94(CH2)mSxe2x80x94, wherein m is as hereinbefore defined, in the presence of an appropriate amount of a suitable oxidising agent (e.g. m-chloroperbenzoic acid) and an appropriate organic solvent.
Compounds of formula VII may be prepared in a similar fashion to compounds of formula I (see, for example, process steps (a) or (b)).
Compounds of formula IX may be prepared by replacement of the OH group of a compound of formula VII with an L2 group under conditions that are well known to those skilled in the art.
Compounds of formula XIV in which R2 and R3 both represent H may be prepared by reduction of a compound of formula XXIII, 
wherein R5a and R5b are as hereinbefore defined, under appropriate conditions (for example conditions such as those described in respect of the preparation of compounds of formula I (process step (c))).
Compounds of formula XIV in which R2 represents OH and R3 does not represent H, may be prepared by reaction of a corresponding compound of formula XXIII as hereinbefore defined, with a compound of formula XVI as hereinbefore defined, under appropriate conditions (for example conditions such as those described hereinbefore for the production of compounds of formula II in which R2 represents OH and R3 represents R3a).
Compounds of formula XIV in which R2 and R3 together represent xe2x80x94Oxe2x80x94(CH2)2xe2x80x94Oxe2x80x94, xe2x80x94(CH2)3xe2x80x94, xe2x80x94(CH2)4xe2x80x94 or xe2x80x94(CH2)5xe2x80x94 may be prepared by reduction of a compound of formula XXIV 
wherein R2a and R3a together represent xe2x80x94Oxe2x80x94(CH2)2xe2x80x94Oxe2x80x94, xe2x80x94(CH2)3xe2x80x94, xe2x80x94(CH2)4xe2x80x94 or xe2x80x94(CH2)5xe2x80x94 and R5a and R5b are as hereinbefore defined in the presence of a suitable reducing agent (e.g. LiAlH4) under conditions that are well known to those skilled in the art.
Compounds of formulae VI, XV, XVII and XXIII may be prepared, advantageously, by reaction of a compound of formula XXV, 
wherein Rz represents H or xe2x80x94C(O)XR1 and R1, R5a, R5b and X are as hereinbefore defined, or a protected derivative thereof, with (as appropriate) either (1) a compound of formula XXVI, 
or a protected derivative thereof, wherein R4, R6, R9, A and B are as hereinbefore defined, or (2) NH3 (or a protected (e.g. benzyl) derivative thereof), in all cases in the presence of a formaldehyde (i.e. an appropriate source of formaldehyde, such as paraformaldehyde or formalin solution).
The formation of compounds of formulae VI, XV, XVII and XXIII may be carried out in this way for example at between room temperature and reflux (depending upon the concentration of the reactants) in the presence of an appropriate solvent (e.g. ethanol or methanol) and, preferably, in the presence of an organic acid (e.g. a C1-6 carboxylic acid, especially acetic acid).
Compounds of formula XXIV may be prepared in accordance with techniques which are well known to those skilled in the art. For example, compounds of formula XXIV in which R2a and R3a together represent xe2x80x94(CH2)3xe2x80x94, xe2x80x94(CH2)4xe2x80x94 or xe2x80x94(CH2)5xe2x80x94 and R5a and R5b are both H may be prepared by reaction of a compound of formula XXVII, 
wherein R2a and R3a together represent xe2x80x94(CH2)3xe2x80x94, xe2x80x94(CH2)4xe2x80x94 or xe2x80x94(CH2)5xe2x80x94, and X, R1, R5a and R5b are as hereinbefore defined with a mixture of phosphoric acid and sulfuric acid, for example at 120xc2x0 C.
Compounds of formulae III, VIII, X, XI, XII, XIII, XIIIA, XVI, XVIII, XIX, XX, XXI, XXII, XXV, XXVI and XXVII, and derivatives thereof, are either commercially available, are known in the literature, or may be obtained either by analogy with the processes described herein, or by conventional synthetic procedures, in accordance with standard techniques, from readily available starting materials using appropriate reagents and reaction conditions.
Substituents on the aryl (e.g. phenyl), and (if appropriate) heterocyclic, group(s) in compounds defined herein may be converted to other substituents using techniques well known to those skilled in the art. For example, nitrobenzene may be reduced to an aminobenzene, hydroxy may be converted to alkoxy, alkoxy may be hydrolysed to hydroxy etc.
The compounds of the invention may be isolated from their reaction mixtures using conventional techniques.
It will be appreciated by those skilled in the art that, in the processes described above, the functional groups of intermediate compounds may be, or may need to be, protected by protecting groups.
Functional groups which it is desirable to protect include hydroxy, amino and carboxylic acid. Suitable protecting groups for hydroxy include trialkylsilyl and diarylalkylsilyl groups (e.g. tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl and alkylcarbonyloxy groups (e.g. methyl- and ethylcarbonyloxy groups). Suitable protecting groups for amino include benzyl, tert-butyloxycarbonyl, 9-fluorenylmethoxycarbonyl or benzyloxycarbonyl. Suitable protecting groups for carboxylic acid include C1-6 alkyl or benzyl esters.
The protection and deprotection of functional groups may take place before or after any of the reaction steps described hereinbefore.
Protecting groups may be removed in accordance with techniques which are well known to those skilled in the art and as described hereinafter.
The use of protecting groups is fully described in xe2x80x9cProtective Groups in Organic Chemistryxe2x80x9d, edited by J W F McOmie, Plenum Press (1973), and xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, 2nd edition, T W Greene and P G M Wutz, Wiley-Interscience (1991).
Persons skilled in the art will appreciate that, in order to obtain compounds of the invention in an alternative, and, on some occasions, more convenient, manner, the individual process steps mentioned herein may be performed in a different order, and/or the individual reactions may be performed at a different stage in the overall route (i.e. substituents may be added to and/or chemical transformations performed upon, different intermediates to those associated hereinbefore with a particular reaction). This will depend inter alia on factors such as the nature of other functional groups present in a particular substrate, the availability of key intermediates and the protecting group strategy (if any) to be adopted. Clearly, the type of chemistry involved will influence the choice of reagent that is used in the said synthetic steps, the need, and type, of protecting groups that are employed, and the sequence for accomplishing the synthesis.
It will also be appreciated by those skilled in the art that, although certain protected derivatives of compounds of formula I, which may be made prior to a final deprotection stage, may not possess pharmacological activity as such, they may be administered parenterally or orally and thereafter metabolised in the body to form compounds of the invention which are pharmacologically active. Such derivatives may therefore be described as xe2x80x9cprodrugsxe2x80x9d. Moreover, certain compounds of formula I may act as prodrugs of other compounds of formula I.
All prodrugs of compounds of formula I are included within the scope of the invention.
Some of the intermediates referred to hereinbefore are novel. According to a further aspect of the invention there is thus provided: (a) a compound of formula II as hereinbefore defined or a protected derivative thereof; (b) a compound of formula IV as hereinbefore defined, or a protected derivative thereof, provided that when R5a and R5b both represent H, then at least one of R2 and R3 represents OR7, OC(O)R8 or C1-4 alkyl, which alkyl group is substituted and/or terminated with one or more nitro or cyano group; (c) a compound of formula VI, as hereinbefore defined, or a protected derivative thereof; (d) a compound of formula XV, as hereinbefore defined, or a protected derivative thereof.
The compounds of the invention are useful because they possess pharmacological activity. They are therefore indicated as pharmaceuticals.
Thus, according to a further aspect of the invention there is provided the compounds of the invention for use as pharmaceuticals.
In particular, the compounds of the invention exhibit myocardial electrophysiological activity, for example as demonstrated in the test described below.
The compounds of the invention are thus expected to be useful in both the prophylaxis and the treatment of arrhythmias, and in particular atrial and ventricular arrhythmias.
The compounds of the invention are thus indicated in the treatment or prophylaxis of cardiac diseases, or in indications related to cardiac diseases, in which arrhythmias are believed to play a major role, including ischaemic heart disease, sudden heart attack, myocardial infarction, heart failure, cardiac surgery and thromboembolic events.
In the treatment of arrhythmias, compounds of the invention have been found to selectively delay cardiac repolarization, thus prolonging the QT interval, and, in particular, to exhibit class III activity. Although compounds of the invention have been found to exhibit class III activity in particular, in the treatment of arrhythmias, their mode(s) of activity is/are not necessarily restricted to this class.
According to a further aspect of the invention, there is provided a method of treatment of an arrhythmia which method comprises administration of a therapeutically effective amount of a compound of the invention to a person suffering from, or susceptible to, such a condition.
The compounds of the invention will normally be administered orally, subcutaneously, intravenously, intraarterially, transdermally, intranasally, by inhalation, or by any other parenteral route, in the form of pharmaceutical preparations comprising the active ingredient either as a free base, a pharmaceutically acceptable ion exchanger or a non-toxic organic or inorganic acid addition salt, in a pharmaceutically acceptable dosage form. Depending upon the disorder and patient to be treated, as well as the route of administration, the compositions may be administered at varying doses.
The compounds of the invention may also be combined with any other drugs useful in the treatment of arrhythmias and/or other cardiovascular disorders.
According to a further aspect of the invention there is thus provided a pharmaceutical formulation including a compound of the invention in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
Suitable daily doses of the compounds of the invention in therapeutic treatment of humans are about 0.05 to 5.0 mg/kg body weight at parenteral administration.
The compounds of the invention have the advantage that they are effective against cardiac arrhythmias.
Compounds of the invention may also have the advantage that they may be more efficacious than, be less toxic than, have a broader range of activity (including exhibiting any combination of class I, class II, class III and/or class IV activity (especially class I, class II and/or class IV activity in addition to class III activity)) than, be more potent than, produce fewer side effects (including a lower incidence of proarrhythmias such as torsades de pointes) than, be more easily absorbed than, or that they may have other useful pharmacological properties over, compounds known in the prior art.
Test A
Primary Electrophysiological Effects In Anaesthetised Guinea Pigs
Guinea pigs weighing between 660 an 1100 g were used. The animals were housed for at least one week before the experiment and had free access to food and tap water during that period.
Anaesthesia was induced by an intraperitoneal injection of pentobarbital (40 to 50 mg/kg) and catheters were introduced into one carotid artery (for blood pressure recording and blood sampling) and into one jugular vein (for drug infusions). Needle electrodes were placed on the limbs for recording of ECGs (lead II). A thermistor was placed in the rectum and the animal was placed on a heating pad, set to a rectal temperature of between 37.5 and 38.5xc2x0 C.
A tracheotomy was performed and the animal was artificially ventilated with room air by use of a small animal ventilator, set to keep blood gases within the normal range for the species. In order to reduce autonomic influences both vagi were cut in the neck, and 0.5 mg/kg of propranolol was given intravenously, 15 minutes before the start of the experiment.
The left ventricular epicardium was exposed by a left-sided thoracotomy, and a custom-designed suction electrode for recording of the monophasic action potential (MAP) was applied to the left ventricular free wall. The electrode was kept in position as long as an acceptable signal could be recorded, otherwise it was moved to a new position. A bipolar electrode for pacing was clipped to the left atrium. Pacing (2 ms duration, twice the diastolic threshold) was performed with a custom-made constant current stimulator. The heart was paced at a frequency just above the normal sinus rate during 1 minute every fifth minute throughout the study.
The blood pressure, the MAP signal and the lead II ECG were recorded on a Mingograph ink-jet recorder (Siemens-Elema, Sweden). All signals were collected (sampling frequency 1000 Hz) on a PC during the last 10 seconds of each pacing sequence and the last 10 seconds of the following minute of sinus rhythm. The signals were processed using a custom-made program developed for acquisition and analysis of physiological signals measured in experimental animals (see Axenborg and Hirsch, Comput. Methods Programs Biomed. 41, 55 (1993)).
The test procedure consisted of taking two basal control recordings, 5 minutes apart, during both pacing and sinus rhythm. After the second control recording, the first dose of the test substance was infused in a volume of 0.2 mL into the jugular vein catheter for 30 seconds. Three minutes later, pacing was started and a new recording was made. Five minutes after the previous dose, the next dose of test substance was administered. Six to ten consecutive doses were given during each experiment.
Data analysis
Of the numerous variables measured in this analysis, three were selected as the most important for comparison and selection of active compounds. The three variables selected were the MAP duration at 75 percent repolarization during pacing, the atrio-ventricular (AV) conduction time (defined as the interval between the atrial pace pulse and the start of the ventricular MAP) during pacing, and the heart rate (defined as the RR interval during sinus rhythm). Systolic and diastolic blood pressure were measured in order to judge the haemodynamic status of the anaesthetised animal. Further, the ECG was checked for arrhythmias and/or morphological changes.
The mean of the two control recordings was set to zero and the effects recorded after consecutive doses of test substance were expressed as percentage changes from this value. By plotting these percentage values against the cumulative dose administered before each recording, it was possible to construct dose-response curves. In this way, each experiment generated three dose-response curves, one for MAP duration, one for AV-conduction time and one for the sinus frequency (RR interval). A mean curve of all experiments performed with a test substance was calculated, and potency values were derived from the mean curve. All dose-response curves in these experiments were constructed by linear connection of the data points obtained. The cumulative dose prolonging the MAP duration by 10% from the baseline was used as an index to assess the class III electrophysiological potency of the agent under investigation (D10).
The invention is illustrated by way of the following examples.